Process for preparing indane carboxylate and cyclopentano [6] pyridine derivatives

ABSTRACT

This invention relates to an improved process for preparing (+) (1S,2R,3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid and pharmaceutically acceptable salts thereof, preferably the ethylene diamine 2:1 salt. 
     This invention relates to novel intermediates useful in preparing (+) (1S,2R,3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid. 
     This invention relates to an improved process for preparing (+) (1S,2R,3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid and pharmaceutically acceptable salts thereof, preferably the disodium salt. 
     This invention relates to novel intermediates useful in preparing (+) (1S,2R,3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylic acid.

This is a divisional of application Ser. No. 08/776,803 filed May 8,1998, now U.S. Pat. No. 6,114,549, which is a 371 of PCT/US96/18082,filed Nov. 8, 1996, which claims benefit to U.S. Provisional ApplicationNo. 60/006,330, filed Nov. 8, 1995.

FIELD OF THE INVENTION

The present invention relates to an improved process for preparingaromatic ring-fused cyclopentane derivatives. Preferably, the presentinvention relates to an improved process for preparing indanecarboxylates and cyclopentano [b]pyridine derivatives. Advantageously,the present invention relates to an improved process for preparing (+)(1S,2R,3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2carboxylicacid and pharmaceutically acceptable salts thereof and (+)(1S,2R,3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid and pharmaceutically acceptable salts thereof. Such compounds aredescribed in International Application No.: PCT/US94/04603—InternationalPublication No. WO 94/25013 published on Nov. 10, 1994 and in U.S. Pat.No. 5,389,620, as being useful as endothelin receptor antagonists. Alsoinvented are novel intermediates useful in preparing these compounds.

BACKGROUND OF THE INVENTION

Processes for the preparation of indane carboxylates, specifically (+)(1S,2R,3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2carboxylicacid and (+)(1S,2R,3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid have previously been described. In particular a multistep processto prepare (+)(1S,2R,3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid in 6% overall yield (not including a racemic separation step) frommethyl 3-(prop-1-yloxy)benzoylacetate and a multistep process to prepare(+)(1S,2R,3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid in 2% overall yield (not including a racemic separation step) frommethyl 3-(prop-1-yloxy)benzoylacetate is reported in InternationalPublication No. WO 94/25013, published Nov. 10, 1994. The syntheses ofthese molecules are complicated by the presence of three chiral centersin each compound.

Processes for the preparation of cyclopentano[b]pyridine derivativeshave previously been described. In particular, multistep processes toprepare cyclopentano[b]pyridine derivatives, in low over all yield, arereported in U.S. Pat. No. 5,389,620.

Thus, there is a need in the art for an economical method to prepareindane carboxylates and cyclopentano[b]pyridine derivatives,specifically (+)(1S,2R,3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid and pharmaceutically acceptable salts thereof and (+)(1S,2R,3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid and pharmaceutically acceptable salts thereof.

The numerous advantages of the presently invented process andintermediates will become apparent upon review of the followingdescription.

SUMMARY OF THE INVENTION

This invention relates to an improved process for preparing aromaticring-fused cyclopentane derivatives.

This invention also relates to novel intermediates useful in preparingaromatic ring-fused cyclopentane derivatives.

This invention relates to an improved process for preparing indanecarboxylates.

This invention also relates to novel intermediates useful in preparingindane carboxylates.

This invention relates to an improved process for preparingcyclopentano[b]pyridine derivatives.

This invention also relates to novel intermediates useful in preparingcyclopentano[b]pyridine derivatives.

This invention relates to an improved process for preparing (+)(1S,2R,3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid and pharmaceutically acceptable salts thereof, preferably theethylene diamine 2:1 salt.

This invention relates to novel intermediates useful in preparing (+)(1S,2R,3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid.

This invention relates to an improved process for preparing (+)(1S,2R,3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid and pharmaceutically acceptable salts thereof, preferably thedisodium salt.

This invention relates to novel intermediates useful in preparing (+)(1S,2R,3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise defined, the term ‘aromatic ring-fused cyclopentanederivatives’ as used herein, is meant to refer to the racemic compoundsof Formula (1):

wherein A, B, C and D are carbon atoms or three of A, B, C and D arecarbon atoms and one is a nitrogen atom;

R¹ is

 where

R³ and R⁴ are independently H, OH, protected OH, C₁₋₈alkoxy, Br, F, I,Cl, CF₃ or

C₁₋₆alkyl and R⁵ is —OCH₂CO₂H or —OCH₂CH₂OH;

R² is

where R³ and R⁴ are as indicated above and

Z is H, OH, or C₁₋₅alkoxy;

or a pharmaceutically acceptable salt thereof.

Preferred among the racemic compounds of Formula (1) are the compoundsof Formula (17):

wherein A, B, C, D, R¹, R² and Z are as described in Formula (1);

or a pharmaceutically acceptable salt thereof.

By the term indane carboxylates as used herein is meant the racemiccompounds of Formula (2):

wherein R¹, R² and Z are as described in Formula (1);

or a pharmaceutically acceptable salt thereof.

Preferred among the racemic compounds of Formula (2) are the compoundsof Formula (18):

wherein R¹, R² and Z are as described in Formula (1);

or a pharmaceutically acceptable salt thereof.

By the term cyclopenteno[b]pyridine derivatives as used herein is meantthe racemic compounds of Formula (3):

wherein three of A, B, C and D are carbon atoms and one is a nitrogenatom; and

R¹, R² and Z are as described in Formula (1);

or a pharmaceutically acceptable salt thereof.

Preferred among the racemic compounds of Formula (3) are the compoundsof Formula (19):

wherein three of A, B, C and D are carbon atoms and one is a nitrogenatom; and

R¹, R² and Z are as described in Formula (1);

or a pharmaceutically acceptable salt thereof.

In Formula (3) compounds, in Formula (19) compounds and in Formula (1)compounds when one of A, B, C or D is a nitrogen atom, preferably A isnitrogen.

Pharmaceutically acceptable salts of the compounds of Formulas (1), (2),(3), (17), (18) and (19) are formed where appropriate by methods wellknown to those of skill in the art.

Pharmaceutically acceptable salts of (+)(1S,2R,3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid and (+)(1S,2R,3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid are formed where appropriate by methods well known to those ofskill in the art.

The term (+)(1S,2R,3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid as used herein utilizes standard chemical terminology and refers toa compound of the structure

The term (+)(1S,2R,3S)-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid ethylene diamine salt (2:1) as used herein utilizes standardchemical terminology and refers to Compound (i)

The term (+)(1S,2R,3S)-3-(2-carboxymethoxy4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid as used herein utilizes standard chemical terminology and refers toa compound of the structure (Y)

The term (+)(1S,2R,3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid disodium salt as used herein utilizes standard chemical terminologyand refers to Compound (g)

The indane carboxylates of Formula (18) of the current invention areprepared by methods outlined in the Schemes below and in the Examplesfrom compounds of Formula (4):

where R is H, OH, C₁₋₅alkoxy (preferably n-PrO) or a protected oxygroup, such as benzyloxy. Compounds of Formula (4) are known or can beprepared from readily available starting materials by those skilled inthe art.

The compounds of Formula (4) can be converted into the compounds ofFormula (a)

where R is as described above, by known methods such as those describedin International Publication No. WO 94/25013, published Nov. 10, 1994 inExample 1, section b) on page 20.

By the term ‘protected oxy group’ and ‘protected OH’ as used herein, ismeant any conventional blocking group in the art such as described in“Protective Groups in Organic Synthesis” by Theodora W. Greene,Wiley-Interscience, 1981, New York, provided that such protected oxygroups or such protected OH do not include moieties that renderinoperative the presently invented process. A preferred protected oxygroup for use herein is benzyloxy. A preferred protected OH for useherein is benzyloxy.

Further, when necessary or desired, R can be converted to a substituentof Z. Reactions to convert R to Z are performed on products of thesynthetic pathways disclosed or claimed herein or, where appropriate orpreferable on certain intermediates in these synthetic pathways. Forexample, hydroxyl groups can be converted into C₁₋₅alkoxy groups byalkylation. Protected oxy groups can be deprotected and further reactedto form a substituent of Z.

The present invention provides an improved process for the production ofindane carboxylates of Formula (18) as indicated in Schemes 1 to 3below.

Scheme 1 outlines formation of indane carboxylates wherein R⁵ is—OCH₂CO₂H, preferably the disodium salt, Compound (g). As used in Scheme1, R³ and R⁴ are as described in Formula (1) and R is as described inFormula (4). Compounds of Formula (b) are prepared by treating compoundsof Formula (a) with a phenol under acidic conditions. Compounds ofFormula (c), as the predominately pure enantiomer, are prepared bycatalytic hydrogenation of Formula (b) compounds using a chiral catalystsuch as[(S)-(−)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl]chloro(p-cymene)rutheniumchloride (as used herein, Ru-(S)-(−)-BINAP) at approx. 1-5 atm H₂,(Bicyclo[2.2.]hepta-2,5-diene)[2S,3S)-bis(diphenylphosphino)butane]-rhodium(I)perchlorate (as used herein, Rh-(S,S)(Chiraphos)(NBD)ClO₄) at approx.400 psi H₂ or preferably, the catalyst prepared by combining [Rh(COD)Cl₂with S,S-Chiraphos, at approx. 180-300 psi. Compounds of Formula (d), asused herein Formula (d) compounds refer to the indicated alcoholdiastereomers, are prepared by

combining Formula (c) compounds with the indicated piperonal in an aldolreaction, most preferably by using titanium (IV) chloride in thepresence of a base, preferably a hindered amine base, such asN,N-diisopropylethylamine. Formula (d) compounds are treated with anacid to cause Friedel-Crafts alkylation to give the predominately pureenantiomer as Formula (e) compounds. Treatment of Formula (e) compoundswith base in the presence of methanol and methyl bromoacetate gives thediester as Formula (f) compounds. Saponification of Formula (f)compounds affords the diacid (preferably Compound Y as used herein)which is treated with sodium hydroxide to give Formula (5) compounds(preferably Compound (g) as used herein).

Scheme 2 outlines formation of indane carboxylates wherein R⁵ is—OCH₂CH₂OH, preferably the ethylene diamine salt (2:1) of Compound (i).As used in Scheme 2, R³ and R⁴ are as described in Formula (1) and R isas described in Formula (4). Formula (e) compounds from Scheme 1 aretreated with base in the presence of methanol to give the phenolesterFormula (h) compounds. Alkylation of Formula (h) compounds followed bysaponification with lithium hydroxide monohydrate affords the acid(preferably Compound (X) as used herein), which is treated with ethylenediamine to give Formula (6) compounds.

In an alternative aspect of the invention novel intermediates of Formula(c) and Formula (d) are prepared according to Scheme 3 below.

Scheme 3 outlines a process for the formation of compounds of Formula(c) and compounds of Formula (d). As used in Scheme 3, R³ and R⁴ are asdescribed in Formula (1), provided that R³ and R⁴ are not Br, I or Cl,and R is as described in Formula (4). Compounds of Formula (j) can beprepared by treating a compound of the formula HX_(c), where HX_(c) isas described below, with lithium bis(trimethylsilyl)amide with thesubsequent addition of an appropriately substituted(E)-3-phenyl-2-propenoyl chloride compound. Compounds of Formula (1) areprepared by treating cuprous bromide-dimethyl sulphide complex indimethylsulphide/THF with an appropriate1-magnesiumbromide-2-benzyloxybenzene compound, followed by the additionof a compound of Formula (j). The Formula (1) compound is treated withpalladium on carbon in a hydrogen atmosphere to give a compound ofFormula (c).

As used in Scheme 3 compounds of Formula (m) are prepared by treatingcuprous bromide-dimethyl sulphide complex in dimethylsulphide/THF withan appropriate 1-magnesiumbromide-2-benzyloxybenzene compound, followedby the addition of a compound of Formula (j), followed by the additionof piperonal. Formula (m) compounds are treated with palladium on carbonin a hydrogen atmosphere to give Formula (d) compounds.

As used in the specification and in the claims the term X_(c) means achiral auxiliary. By the term “chiral auxiliary” as used in thespecification and in the claims is meant a non-racemic functional groupthat imparts a diastereoselective reaction at a remote prochiral centerof a molecule. Chiral auxiliaries are used herein are formed by reactionwith a compound of the formula HX_(c) wherein X_(c) is as describedabove. Examples of HX_(c) as used herein include: 8-phenylmenthol(5-methyl-2-(1-methyl-1-phenyl-ethyl)-cyclohexanol, such as described inD. Comins et al. J. Org. Chem., vol. 58, 4656 (1993)), N-substitutedbornane-2, 10-sultams (e.g.,10,10-dimethyl-3-thia-4-aza-tricyclo[5.2.1.0^(1.5)]decane 3,3-dioxide.such as described in W. Oppolzer J. Am. Chem. Soc., 112 2767 (1990)),preferably, 4-substituted or 4,5-substituted 2-oxazolidinones derivedfrom amino acid derivatives such as phenylglycinol or valinol (e.g.,4-phenyl-2-oxo-oxazolidin-3-yl or 4-isopropyl-2-oxo-oxazolidin-3-yl,respectively, such as described in D. Evans et al. J. Am. Chem. Soc.,109, 6881 (1987) and in D. Evans et al. Tet. Lett., 28, 1123 (1990))and, most preferably, 4-substituted or 4,5-substituted2-imidazolidinones derived from compounds such as ephedrine (e.g.,3,4-dimethyl-5-phenyl-2-oxo-imidazolidin-1-yl, such as described in S.E. Drewes, et al. Chem. Ber., 126, 2663 (1993)).

The racemic compounds of Formulas (1), (2) and (3) are preparedaccording to the methods outlined in Schemes (1) and (2) and in theExamples by substituting a compound of Formula (7):

wherein A, B, C and D are carbon atoms or three of A, B, C and D arecarbon atoms and one is a nitrogen atom and R is H, OH, C₁₋₅alkoxy(preferably n-PrO) or a protected oxy group, such as benzyloxy,

for the compound of formula (4) and by substituting the correspondingachiral catalyst for the chiral catalyst disclosed in Scheme 1 for thepreparation of Formula (c) compounds.

Compounds of Formula (7) are known or can be prepared from readilyavailable starting materials by those skilled in the art.

The compounds of Formula (7) can be converted into the compounds ofFormula (8)

where A, B, C, D and R are as described in Formula (7), by known methodssuch as those described in International Publication No. WO 94/25013,published Nov. 10, 1994 in Example 1, section b) on page 20.

Thus, the compounds of Formula (8) are utilized in Schemes 1 and 2,using an achiral catalyst in the Formula (b) to Formula (c)transformation, to prepare compounds of Formula (1) and intermediatesuseful in preparing compounds of formula (1). The compounds of Formula(a) are utilized in Schemes 1 and 2, by substituting an achiral catalystin the Formula (b) to Formula (c) transformation, to prepare compoundsof Formula (2) and intermediates useful in preparing compounds offormula (2). The compounds of Formula (8), wherein three of A, B, C andD are carbon atoms and one is a nitrogen atom, are utilized in Schemes 1and 2, using an achiral catalyst in the Formula (b) to Formula (c)transformation, to prepare compounds of Formula (3) and intermediatesuseful in preparing compounds of formula (3).

The cyclopenteno[b]pyridine derivatives of Formula (19) of the currentinvention are prepared according the methods outlined in Schemes 1 to 3and in the

Examples from compounds of Formula (8) wherein three of A, B, C and Dare carbon atoms and one is a nitrogen atom. Preferred among Formula (7)and Formula (8) compounds when a nitrogen is present are those wherein Ais nitrogen.

The aromatic ring-fused cyclopentane derivatives of Formula (17) of thecurrent invention are prepared according the methods outlined in Schemes1 to 3 and in the Examples from compounds of Formula (8) wherein A, B, Cand D are carbon atoms or three of A, B, C and D are carbon atoms andone is a nitrogen atom. Preferred among Formula (7) and Formula (8)compounds when a nitrogen is present are those wherein A is nitrogen.

Prepared in synthesizing the indane carboxylates of Formula (18),preferably compound (g) and Compound (i), are the novel intermediates ofFormula (b):

wherein R³ and R⁴ are as described in Formula (1) and R is as describedin Formula (4).

Also prepared in synthesizing the indane carboxylates of Formula (18),preferably Compound (g) and Compound (i), are the novel intermediates ofFormula (c):

wherein R³ and R⁴ are as described in Formula (1) and R is as describedin Formula (4).

Also prepared in synthesizing the indane carboxylates of Formula (18),preferably Compound (g) and Compound (i), are the novel intermediates ofFormula (d):

wherein R³ and R⁴ are as described in Formula (1) and R is as describedin Formula (4).

Also prepared in synthesizing the indane carboxylates of Formula (18),preferably Compound (g) and Compound (i), are the novel intermediates ofFormula (e):

wherein R³ and R⁴ are as described in Formula (1) and R is as describedin Formula (4).

Also prepared in synthesizing the indane carboxylates of Formula (18),preferably Compound (g) and Compound (i), are the novel intermediates ofFormula (f):

wherein R³ and R⁴ are as described in Formula (1) and R is as describedin Formula (4).

Also prepared in synthesizing the indane carboxylates of Formula (18),preferably Compound (i), are the novel intermediates of Formula (h):

wherein R³ and R⁴ are as described in Formula (1) and R is as describedin Formula (4).

Also prepared in synthesizing the indane carboxylates of Formula (18),preferably Compound (g) and Compound (i), are the novel intermediates ofFormula

wherein R is as described in Formula (4).

Also prepared in synthesizing the indane carboxylates of Formula (18),preferably Compound (g) and Compound (i), are the novel intermediates ofFormula (1):

wherein R³ and R⁴ are as described in Formula (1) and R is as describedin Formula (4).

Also prepared in synthesizing the indane carboxylates of Formula (18),preferably Compound (g) and Compound (i), are the novel intermediates ofFormula (m):

wherein R³ and R⁴ are as described in Formula (1) and R is as describedin Formula (4).

Prepared in synthesizing the aromatic ring-fused cyclopentanederivatives of Formula (1) are the novel intermediates of Formula (9):

wherein A, B, C and D are carbon atoms or three of A, B, C and D arecarbon atoms and one is a nitrogen atom, R³ and R⁴ are as described inFormula (1) and R is as described in Formula (4).

Prepared in synthesizing the cyclopenteno[b]pyridine derivatives ofFormula (19) are intermediates of Formula (9) where three of A, B, C andD are carbon atoms and one is a nitrogen atom, R³ and R⁴ are asdescribed in Formula (1) and R is as described in Formula (4).

Also prepared in synthesizing the cyclopenteno[b]pyridine derivatives ofFormula (19) are the novel intermediates of Formula (10):

wherein three of A, B, C and D are carbon atoms and one is a nitrogenatom, R³ and R⁴ are as described in Formula (1) and R is as described inFormula (4).

Also prepared in synthesizing the cyclopenteno[b]pyridine derivatives ofFormula (19) are the novel intermediates of Formula (11):

wherein three of A, B, C and D are carbon and one is nitrogen, R³ and R⁴are as described in Formula (1) and R is as described in Formula (4).

Also prepared in synthesizing the cyclopenteno[b]pyridine derivatives ofFormula (19) are the novel intermediates of Formula (12):

wherein three of A, B, C and D are carbon and one is nitrogen, R³ and R⁴are as described in Formula (1) and R is as described in Formula (4).

Also prepared in synthesizing the cyclopenteno[b]pyridine derivatives ofFormula (19) are the novel intermediates of Formula (13):

wherein three of A, B, C and D are carbon and one is nitrogen, R³ and R⁴are as described in Formula (1) and R is as described in Formula (4).

Also prepared in synthesizing the cyclopentenofblpyridine derivatives ofFormula (19) are the novel intermediates of Formula (14):

wherein three of A, B, C and D are carbon and one is nitrogen, R³ and R⁴are as described in Formula (1) and R is as described in Formula (4).

Also prepared in synthesizing the cyclopenteno[b]pyridine derivatives ofFormula (19) are the novel intermediates of Formula (15):

wherein three of A, B, C and D are carbon atoms and one is a nitrogenatom and R is as described in Formula (4).

Also prepared in synthesizing the cyclopenteno[b]pyridine derivatives ofFormula (19) are the novel intermediates of Formula (16):

wherein three of A, B, C and D are carbon atoms and one is a nitrogenatom; R³ and R⁴ are as described in Formula (1) and R is as described inFormula (4).

Also prepared in synthesizing the cyclopenteno[b]pyridine derivatives ofFormula (19) are the novel intermediates of Formula (25):

wherein three of A, B, C and D are carbon atoms and one is a nitrogenatom; R³ and R⁴ are as described in Formula (1) and R is as described inFormula (4).

Prepared in synthesizing the aromatic ring-fused cyclopentanederivatives of Formula (1) are the novel intermediates of Formula (20):

wherein A, B, C and D are carbon atoms or three of A, B, C and D arecarbon atoms and one is nitrogen, R³ and R⁴ are as described in Formula(1) and R is as described in Formula (4).

Also prepared in synthesizing the aromatic ring-fused cyclopentanederivatives of Formula (1) are the novel racemic intermediates ofFormula (21):

wherein A, B, C and D are carbon atoms or three of A, B, C and D arecarbon atoms and one is a nitrogen atom; R³ and R⁴ are as described inFormula (1) and R is as described in Formula (4).

Also prepared in synthesizing the aromatic ring-fused cyclopentanederivatives of Formula (1) are the novel racemic intermediates ofFormula (22):

wherein A, B, C and D are carbon atoms or three of A, B, C and D arecarbon atoms and one is a nitrogen atom; R³ and R⁴ are as described inFormula (1) and R is as described in Formula (4).

Also prepared in synthesizing the aromatic ring-fused cyclopentanederivatives of Formula (1) are the novel racemic intermediates ofFormula (23):

wherein A, B, C and D are carbon atoms or three of A, B, C and D arecarbon atoms and one is a nitrogen atom; R³ and R⁴ are as described inFormula (1) and R is as described in Formula (4).

Also prepared in synthesizing the aromatic ring-fused cyclopentanederivatives of Formula (1) are the novel racemic intermediates ofFormula (24):

wherein A, B, C and D are carbon atoms or three of A, B, C and D arecarbon atoms and one is a nitrogen atom; R³ and R⁴ are as described inFormula (1) and R is as described in Formula (4).

All of the starting materials and reagents used herein are known andreadily available or can be easily made from known and readily availablereagents.

For example, Rh-(S,S)(Chiraphos)(NBD)ClO₄.THF and Ru-(S)-(−)BINAP areobtained from the Aldrich chemical company Milwaukee, Wis.

For example, (E)-3-(3′-propyloxyphenyl)-2-propenoyl chloride, used inExample 3 (i), can be prepared from commercially available3-hydroxybenzaldehyde by reacting 3-hydroxybenzaldehyde with1-iodopropane to give 3-propyloxy benzaldehyde. 3-Propyloxy benzaldehydeis then reacted with malonic acid to give the corresponding propenonicacid which is subsequently converted into(E)-3-(3′-propyloxyphenyl)-2-propenoyl chloride by reaction with oxalylchloride.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following Examples are, therefore, to beconstrued as merely illustrative and not a limitation of the scope ofthe present invention in any way.

EXAMPLES Example 1

Corresponding to Scheme 1

(+)(1S,2R,3S)-3-(2-Carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid disodium salt (i). Methlyl 3-hydroxybenzoylacetate (a compound ofFormula (a))

THF (10.0 L), 60% NaH (2.00 kg), and dimethyl carbonate (6.50 kg) werecharged to a reaction vessel and stirred while heating to 55-60° C. Asolution of 3-hydroxyacetophenone (2.70 kg) (a compound of Formula (4))in THF (10.0 L) was added to the reaction mixture over 75 minutes,maintaining the reaction temperature at 55-60° C. during the addition.After 20 minutes, TLC indicated that the reaction was complete, so itwas cooled to 20-25° C. and quenched carefully with 2.9 M hydrochloricacid (20.0 L). The mixture was extracted three times with toluene(3×10.0 L). All three organic layers were combined, washed with oncesaturated aqueous NaCl (10.0 L), concentrated by vacuum distillation toabout 5 L, and cooled to 35-40° C. The top phase (toluene and themineral oil from the NaH) was removed and discarded, and the bottomlayer (3-hydroxybenzoylacetate (a compound of Formula (a)) and toluene,5.6 kg total) was used as is in the preparation of4-[3-(hydroxy)phenyl]-7-methoxycoumarin (a compound of Formula (b)). Asample from the product layer was concentrated in vacuo to remove thetoluene, after which it gave the following 300 MHz ¹H NMR (CDCl₃): δ3.75(s, 3 H), 4.00 (s, 2 H), 6.51 (br s, 1 H), 7.10 (dd, J₁=2 Hz, J₂=8 Hz, 1H), 7.32 (t, J=8 Hz, 1 H), 7.45 (m, 2 H).

(ii). 4-[3′-(hydroxy)phenyl]-7-methoxycoumarin (a compound of Formula(b))

The solution of methyl 3-hydroxybenzoylacetate (about 4.0 kg) andtoluene (total weight of solution 5.6 kg) from the step above wascharged to a reaction vessel along with 3-methoxyphenol (2.55 kg). Themixture was stirred vigorously at 0° C. while 27 M sulfuric acid (5.55L) was added over 5 minutes. The resulting dark solution was warmed to25° C. When the reaction began to thicken (40 minutes), methanol (21.8L) was added. The addition was exothermic. Continued stirring (15minutes) yielded a smooth, brown slurry which was cooled to 5° C. over25 minutes, stirred for one hour, then filtered. The filter cake waswashed with methanol (5.50 L) and dried under vacuum at 45-50° C. togive 3.70 kg (13.8 mol, 70% yield for two steps) of4-[3′-(hydroxy)phenyl]-7-methoxycoumarin (a compound of Formula (b)).

300 MHz ¹H NMR (DMSO-d₆): δ3.86 (s, 3 H), 6.18 (s, 1 H), 6.90 (m, 4 H),7.07 (d, J=2 Hz, 1 H), 7.32 (d, J=9 Hz, 1 H), 7.38 (d, J=10 Hz, 1 H).

(iii). 4-[3′-(Prop-1-yloxy)phenyl]-7-methoxycoumarin (a compound ofFormula (b))

4-[3′-(hydroxy)phenyl]-7-methoxycoumarin (1.78 kg) and K₂CO₃ (1.65 kg)were suspended in acetonitrile (7.20 L) and N,N-dimethylformamide (1.80L) and the mechanically stirred mixture was heated to 65° C. When thereaction had reached 65° C., neat n-propylbromide (1.48 kg) was addedand the mixture was stirred another 21 hours. The slurry was heated to88-109° C. and concentrated by distillation. When 6.8-7.0 L ofdistillate had been removed, the slurry was cooled to 40° C. and dilutedwith water (14.4 L) and stirred while cooling slowly to 20° C. Theslurry was filtered to collect the title compound as a pink, amorphoussolid, which was washed with water (2.0 L). The air-dried product wasrecrystallized from a mixture of hexanes (11.9 L) and isopropanol (6.2L) at 50° C. Filtration at 22° C. gave a very pale pink, crystallinesolid which was washed with hexanes (250 mL) and air-dried. Weight=1.70kg (5.58 mol, 83%). A second crop of product was isolated from thepartially concentrated mother liquors; the light pink, crystalline solidweighed 307 g (0.989 mol, 15%).

300 MHz ¹H NMR (CDCl₃) δ1.05 (t, J=7 Hz, 3 H), 1.83 (m, J=7 Hz, 2 H),3.88 (s, 3 H), 3.96 (t, J=7 Hz, 2 H), 6.21 (s, 1 H), 6.79 (dd, J₁=2 Hz,J₂=9 Hz, 1 H), 6.88 (d, J=2 Hz, 1 H), 6.94 (m, 3 H), 7.40 (t, J=8 Hz, 1H), 7.42 (d, J=9 Hz, 1 H).

(iiia). 4-[3′-(Prop-1-yloxy)phenyl]-7-methoxycoumarin (a Compoundformula (b)); (alternative preparation)

A solution of methyl 3-(prop-1-yloxy)benzoylacetate (745 g) (a compoundof Formula (a)) in 1,2-dichloroethane was combined under nitrogen with asolution of 3-methoxyphenol (488 g) in 1,2-dichloroethane (2.5 L) andcooled to 0° C. Concentrated H₂SO₄ (626 mL) was added dropwise and themixture was stirred vigorously at RT for 90 minutes. Ethyl acetate (3 L)and H₂O (3 L) were added and the layers were equilibrated and separated.The aqueous layer was extracted again with ethyl acetate and thecombined organic layers were washed with H₂O, 5% aqueous Na₂CO₃, 5%aqueous NaOH, H₂O, and brine (2 L each). The organic phase was driedwith MgSO₄ and concentrated to dryness to yield 841 g (86%) of4-[3-(prop-1-yloxy)phenyl]-7-methoxycoumarin. The product wasrecrystallized from ethanol/isopropanol followed by ethylacetate/isopropanol to give 533 g (63% recovery) of4-[3′-(prop-1-yloxy)phenyl]-7-methoxycoumarin.

300 MHz ¹H NMR (CDCl₃) δ1.05 (t, J=7 Hz, 3 H), 1.83 (m, J=7 Hz, 2 H),3.88 (s, 3 H), 3.96 (t, J=7 Hz, 2 H), 6.21 (s, 1 H), 6.79 (dd, J₁=2 Hz,J₂=9 Hz, 1 H), 6.88 (d, J=2 Hz, 1 H), 6.94 (m, 3 H), 7.40 (t, J=8 Hz, 1H), 7.42 (d, J=9 Hz, 1 H).

(iv). 4S-4-[3′-(Prop-1-yloxy)phenyl]-7-methoxy-3,4-dihydrocoumarin (acompound of Formula (c)); (preferred preparation)

A clean 1 L autoclave is charged with4-[3′-(prop-1-yloxy)phenyl]-7-methoxycoumarin (62.0 g; 0.20 mol), abs.methanol (565 mL), [Rh(COD)Cl]₂ (245 mg; 0.5 mmol; 0.25 mol %),S,S-Chiraphos (427 mg; 1.0 mmol; 0.5 mol %) and 4 N NaOH (100 mL; 0.4mol; 2 eq). The sealed vessel is purged with 3×200 psi N₂ and 3×200 psiH₂. The stirred reaction is run at 50° C., 180-300 psi H₂ for 18-24 h.Cool and remove from the vessel.

The methanol solution is concentrated in vacuo to near dryness. Theresidual brown oil is dissolved in H₂O (500 mL) and washed with toluene(2×200 mL). The toluene phases are combined and washed with 1 N NaOH(100 mL). The 1 N NaOH phase is combined with the original aqueousphase. This is acidified to pH 1-2 with 6 N HCl and extracted withtoluene (3×300 mL). The combined toluene extracts are washed with sat.NaCl soln (400 mL), dried over MgSO₄ (50 g), filtered, and concentratedin vacuo to 300-400 mL.

The toluene solution is treated with p-toluenesulfonic acid monohydrate(2.0 g) and heated to 50° C. for 1 h, or until HPLC indicates thatlactonization is complete. The solution is cooled, washed with sat. NaCLsoln (300 mL), dried over MgSO₄ (30 g), filtered, slurried with florisil(10 g) for 15 min, filtered, and concentrated in vacuo to near drynessas a clear oil. Addition of hexanes (300 mL), to the stirred oil resultswithin 15 min in a white filterable solid of4S-4-[3′-(Prop-1-yloxy)phenyl]-7-methoxy-3,4-dihydrocoumarin (53.1 g;85% yield). Chiral HPLC indicates 91.5% ee.

300 MHz ¹H NMR (CDCl₃), δ1.02 (t, J=7 Hz, 3 H), 1.78 (m, J=7 Hz, 2 H),3.02 (m, 2H), 3.80 (s, 3 H), 3.88 (t, J=7 Hz, 2 H), 4.24 (t, J=7 Hz, 1H), 6.63 (dd, J₁=2 Hz, J₂=8 Hz, 1 H), 6.68 (m, 2 H), 6.72 (br d, J=8 Hz,1 H), 6.80 (ddd, J₁=0.6 Hz, J₂=2 Hz, J₃=8 Hz, 1 H), 6.89 (d, J=8 Hz, 1H), 7.24 (t, J=8 Hz, 1 H).

(iva). 4S-4-[3′-(Prop-1-yloxy)phenyl]-7-methoxy-3,4-dihydrocoumarin (acompound of Formula (c)); (alternative preparation)

A solution of 4-[3′-(prop-1-yloxy)phenyl]-7-methoxycoumarin (12.41 g)and[(S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl]chloro(p-cymene)rutheniumchloride (520 mg) in MeOH (94 mL) and 4 N NaOH (20 mL) was shaken at 50°C. under an atmosphere of 3-5 psi H₂. After 18 h the reaction was cooledto 23° C., purged with N₂, and concentrated in vacuo to approximately ¼the original volume. The remaining solution was partitioned between H₂O(100 mL) and toluene (100 mL).

The phases were separated, the aqueous phase was washed with toluene (75mL), and the combined toluene phases were extracted once with 5% aqueousNaOH. The combined aqueous phases were cooled to 5° C., stirred withtoluene (75 mL), and the mixture was acidified to pH 1 with precooled 6N HCl. After separation, the aqueous phase was extracted with toluene(2×75 mL). The toluene phases were combined, washed with brine (100 mL),dried over MgSO₄ (15 g), filtered, and concentrated in vacuo toapproximately ½ volume. The remaining solution was treated withp-toluenesulfonic acid monohydrate (0.38 g), and stirred at 50° C. for 1h. The solution was cooled to 23° C., washed with brine (100 mL), driedover MgSO₄ (15 g), filtered, and slurried with Florisil for 15 min.Filtration and concentration in vacuo yielded4S-4-[3′-(prop-1-yloxy)phenyl]-7-methoxy-3,4-dihydrocoumarin (10.6 g,85%, 84% ee) as a colorless oil which solidified on standing.

(ivb). 4S-4-[3′-(Prop-1-yloxy)phenyl]-7-methoxy-3,4-dihydrocoumarin (acompound of Formula (c)); (alternative preparation)

A solution of 4-[3′-(prop-1-yloxy)phenyl]-7-methoxycoumarin (12.4 g;40.0 mmol) and[(2S,3S)bis(diphenylphosphino)butane](Bicyclo[2.2.1]hepta-2,5-diene)rhodiumperchlorate tetrahydrofuran complex (65 mg) in methanol (94 mL) and 4.0N NaOH (20 mL) was stirred at 50° C. under 400 psi H₂. After 18 h. thereaction was cooled to 23° C. and purged with N₂. The clear orange-brownsolution (which darkens on exposure to air) was concentrated in vacuo toapproximately ¼ the original volume. The remaining solution waspartitioned between H₂O (100 mL) and toluene (100 mL). The phases wereseparated, the aqueous phase was washed with toluene (75 mL), and thecombined toluene phases were extracted with 5% aqueous NaOH (30 mL). Thecombined aqueous phases were cooled to 5° C., stirred with toluene (75mL), and the mixture was acidified to pH 1 with precooled 6 N HCl. Afterseparation, the aqueous phase was extracted with toluene (3×75 mL). Thetoluene phases were combined, washed with brine (100 mL), dried overMgSO₄ (15 g), filtered, and concentrated in vacuo to approximately ½volume. The remaining solution was treated with p-toluenesulfonic acidmonohydrate (0.38 g), and stirred at 50° C. for 1 h. The solution wascooled to 23° C., washed with brine (100 mL), dried over MgSO₄ (15 g),filtered, and slurried with florisil (5.0 g) for 15 min. Filtration andconcentration in vacuo yielded4S-4-[3′-(prop-1-yloxy)phenyl]-7-methoxy-3,4-dihydrocoumarin (9.62 g,77%, 84% ee) as a colorless oil which solidified on standing.

(v).3S,4S-3-(1′-Piperonylalcohol)-4-[3′-(prop-1-yloxy)phenyl]-7-methoxy-3,4-dihydrocoumarin(a compound of Formula (d))

A solution of4S-4-[3′-(prop-1-yloxy)phenyl]-7-methoxy-3,4-dihydrocoumarin (72.0 g,92% ee), piperonal (35.0 g), and N,N-diisopropylethylamine (44.6 g) inCH₂Cl₂ (720 mL) under nitrogen was cooled to −28° C. The solution wastreated with neat TiCl₄ (27.9 mL) added over approximately 30 minuteswhile maintaining the temperature at about −25° C. After stirring about1.5 hours, the reaction was quenched saturated aqueous NH₄Cl (240 mL)and water (480 mL) and warmed to 15° C. The layers were equilibrated andseparated. The organic layer was washed with water (720 mL) and brine(720 mL), dried with MgSO₄, and concentrated to give a brittle foam (107g) consisting of a 1:1 mixture of the two alcohol diastereomers of3S,4S-3-(1′-Piperonylalcohol)-4-[3′-(prop-1-yloxy)phenyl]-7-methoxy-3,4-dihydrocoumarin.If desired, the dried organic phase may be used directly in the nextreaction, without first concentrating to a foam.

300 MHz ¹H NMR, diastereomer A (CDCl₃) δ0.99 (t, J=7 Hz, 3 H), 1.74 (m,J=7 Hz, 2 H), 2.62 (br s, 1 H), 3.28 (dd, J₁=3 Hz, J₂=9 Hz, 1 H), 3.80(m, 3 H), 3.83 (s, 3 H), 4.55 (d, J=9 Hz, 1 H), 5.98 (s, 2 H), 6.43 (brs, 1 H), 6.48 (d, J=7 Hz, 1 H), 6.70 (m, 4 H), 6.78 (d, J=8 Hz, 1 H),6.82 (d, J=1 Hz, 1 H), 6.88 (d, J=9 Hz, 1 H), 7.14 (t, J=8 Hz, 1 H).

300 MHz ¹H NMR, diastereomer B (CDCl₃) δ1.01 (t, J=7 Hz, 3 H), 1.76 (m,J=7 Hz, 2 H), 2.71 (br s, 1 H), 3.32 (dd, J₁=4 Hz, J₂=8 Hz, 1 H), 3.83(t, J=7 Hz, 2 H), 3.82 (s, 3 H), 4.44 (d, J=4 Hz, 1 H), 4.70 (br d, J=7Hz, 1 H), 5.94 (s, 2 H), 6.53 (br s, 1 H), 6.57 (d, J=8 Hz, 1 H), 6.68(m, 5 H), 6.81 (d, J=1 Hz, 1 H), 6.98 (d, J=9 Hz, 1 H), 7.16 (t, J=8 Hz,1 H).

(va).3S,4S-3-(1′-Piperonylalcohol)-4-[3′-(prop-1-yloxy)phenyl]-7-methoxy-3,4-dihydrocoumarin(a compound of Formula (d)); (alternative preparation)

A solution of4S-4-[3-(prop-1-yloxy)phenyl]-7-methoxy-3,4-dihydrocoumarin (51.5 g, 84%ee) in CH₂Cl₂ (400 mL) under nitrogen was cooled in a dry ice/acetonebath. The solution was treated with TiCl₄ (198 mL of a 1 M solution inCH₂Cl₂) added over 25 minutes followed by neat N,N-diisopropylethylamine(27.8 g) added over 5 minutes. Solid piperonal (25.8 g) was added to thereaction all at once and stirred 1.5 hours. The reaction was quenched 1N HCl (400 mL) and the layers were equilibrated and separated. Theaqueous layer was extracted with CH₂Cl₂ (200 mL) and the combinedorganic layers were washed with brine (600 mL), dried with MgSO₄, thedried organic phase is concentrated to yield3S,4S-3-(1′-piperonylalchohol)-4-[3-(prop-1-yloxy)phenyl]-7-methoxy-3,4-dihydrocoumarinas a 2:1 mixture of alcohol diastereomers.

(vi).1S,2R,3S-1-Piperonyl-2,3-(7′-methoxy-2′,3′-dihydrocoumarinyl)-5-(prop-1-yloxy)indane(a compound of Formula (e))

A solution of3S,4S-3-(1′-Piperonylalcohol)-4-[3′-(prop-1-yloxy)phenyl]-7-methoxy-3,4-dihydrocoumarin(106 g) in CH₂Cl₂ (850 mL) was heated to 39° C. and treated with neattrifluoroacetic acid (425 mL). The reaction was stirred at about 40° C.for 4.67 hours, then cooled to 20° C. and quenched into 500 mL of icewater. The layers were equilibrated and separated. The organic layer waswashed twice with water (2×500 mL) followed by half-saturated aqueousNaHCO₃ (500 mL) and saturated aqueous NaCl (300 mL). The organic layerwas dried with MgSO₄ and concentrated to give a yellow solid (132 g)that was suspended (partially dissolved) in CH₃CN (1200 mL) and stirredat reflux for 2 hours. The slurry was cooled to room temperature andfiltered to collect the title compound, which was washed with CH₃CN (50mL) and air-dried. The white, crystalline solid (94% ee) weighed 46.8 g(46% yield for two steps).

300 MHz ¹H NMR (CDCl₃) δ1.09 (t, J=7 Hz, 3 H), 1.86 (m, J=7 Hz, 2 H),2.98 (dd, J₁=11 Hz, J₂=14 Hz, 1 H), 3.81 (s, 3 H), 3.99 (t, 2 H), 4.40(m, 2 H), 5.93 (dd, J₁=4 Hz, J₂=1 Hz, 2 H), 6.75 (m, 3 H), 6.79 (s, 1H), 6.82 (dd, J₁=8 Hz, J₂=2 Hz, 1 H), 6.88 (dd, J₁=8 Hz, J₂=2 Hz, 1 H),6.94 (br d, J=8 Hz, 1 H), 7.32 (br s, 1 H), 7.75 (br d, J=8 Hz, 1 H).

(via).1S,2R,3S-1-Piperonyl-2,3-(7′-methoxy-2′,3′-dihydrocoumarinyl)-5-(prop-1-yloxy)indane(a compound of Formula (e)); (alternative preparation)

The solution of3S,4S-3-(1′-piperonylalcohol)-4-[3′-(prop-1-yloxy)phenyl]-7-methoxy-3,4-dihydrocoumarin,from step (va) above before concentration, (800 mL total volume) wascooled in an ice/water bath and maintained under a nitrogen atmosphere.A solution of SnCl₄ in CH₂Cl₂ (176 mL of a 1 M solution) was added tothe reaction over 35 minutes. The reaction was stirred at 3-5° C. for 1hour, then quenched with 800 mL of brine. The layers were equilibratedand separated. The aqueous layer was extracted with CH₂Cl₂ (200 mL) andthe combined organic layers were dried with MgSO,. The dried organicphase was concentrated to give an orange foam (82.2 g) that wasdissolved in CH₃CN (82 mL) and allowed to stand over the weekend. Theresulting crystals were collected by filtration and washed with CH₃CN(70 mL) to give1S,2R,3S-1-piperonyl-2,3-(7′-methoxy-2′,3′-dihydrocoumarinyl)-5-(prop-1-yloxy)indaneas a white solid (8.05 g, 97% ee, 11% yield for steps (iii) and (iv)).

¹H NMR (CDCl₃) of the crude material, δ7.13 (d, 1 H), 6.69-6.82 (m, 5H), 6.48-6.56 (m, 2 H), 6.36 (d, 1H), 5.94 (s, 2 H), 4.98 (d, 1 H),4.5-4.65 (m, 3 H), 3.7-3.85 (m, 8 H), 3.6 (s, 3 H), 3.33 (t, 1 H),1.68-1.80 (m, 2 H), 1.0 (t, 3 H) ppm.

(vii). (+) Methyl(1S,2R,3S)-3-(2-carbomethoxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate(a compound of Formula (f))

1S,2R,3S-1-piperonyl-2,3-(7′-methoxy-2′,3′-dihydrocoumarinyl)-5-(prop-1-yloxy)indane(90 mg) was dissolved in acetone (3.0 mL) at 25° C. K₂CO₃ (139 mg)followed by methanol (0.10 mL) and methylbromoacetate (37 mg) were addedand the mixture was stirred 5 hours at 25° C. Additional methanol (0.40mL) and methylbromoacetate (12 mg) were added during this time. Thereaction was stirred an additional 2 hours at 25° C., then diluted withmethyl-tert-butyl ether (30 mL) and washed with brine (2×25 mL). Theorganic phase was dried with MgSO₄ and concentrated to give (+) methyl(1S,2R,3S)-3-(2-carbomethoxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate(100 mg, 90%) as a viscous oil.

(viii). (+)(1S,2R,3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid disodium salt (Compound (g))

To a solution of (+) Methyl(1S,2R,3S)-3-(2-carbomethoxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate(49.2 g) in isopropanol (1000 mL) and water (48 mL) was added a 50%aqueous solution of sodium hydroxide (179.4 g). The mixture was stirredunder nitrogen for 16 hours then concentrated to approximately 200 mL.Water (400 mL) was added and the solution was extracted with t-butylmethyl ether (300 mL). The aqueous layer was acidified with dilute HCland extracted twice with 300 mL portions of TBNE. The organic layer waswashed 4 times with water (4×200 mL), then concentrated under reducedpressure. Absolute ethanol was added (400 mL) and the solution wasfurther concentrated to approximately 150 mL. The solution was dilutedto 800 mL with absolute ethanol and 60 mL of water. The solution wastitrated to pH=11-12 with 1.25 N sodium hydroxide solution then afterstirring for 15 minutes, concentrated to an oil. Absolute ethanol (250mL) was added and the solution reconcentrated to a solid which wastriturated with hexane, and filtered. The solid was dried to a constantweight to afford (+)(1S,2R,3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid disodium salt.

Example 2

Corresponding to Scheme 2

(+)(1S,2R,3S)-3-[2-(2-Hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid ethylene diamine salt (2:1) (i). (+)Methyl-(1S,2R,3S)-3-(2-hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate(a compound of Formula (h))

1S,2R,3S-1-Piperonyl-2,3-(7′-methoxy-2′,3′-dihydrocoumarinyl)-5-(prop-1-yloxy)indane(20.0 g) (prepared as described in Example 1 (vi)) was suspended intoluene (160 mL) with powdered K₂CO₃ (635 mg, 0.1 equiv) and methanol(120 mL) at room temperature. HPLC of a reaction sample taken after 2hours of stirring showed no starting material remaining,. The reactionwas quenched with water (100 mL) and concentrated to a total volume ofapproximately 200 mL. The mixture was treated with 5% aqueous citricacid (20 mL) and extracted 4 times with toluene (2×40 mL then 2×20 mL).The combined organic phases were washed twice with saturated aqueousNaCl (2×40 mL) and dried by filtration through a pad of MgSO₄.Weight-based assay of the toluene solution versus a reference standardshowed the presence of 21.4 g (100%) of (+)Methyl-(1S,2R,3S)-3-(2-hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate.

(ia). (+)Methyl-(1S,2R,3S)-3-(2-hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate(a compound of Formula (h)); (alternative preparation)

1S,2R,3S-1-Piperonyl-2,3-(7′-methoxy-2′,3′-dihydrocoumarinyl)-5-(prop-1-yloxy)indane(prepared as described in Example 1 (via)) (7.33 g) was dissolved inacetone (75 mL) at 25° C. K₂CO₃ (11.4 g) and methanol (10 mL) were addedand the mixture was stirred at 25° C. for 2 hours. The reaction wasconcentrated to about 80% of its original volume, H₂O (150 mL) wasadded, and the solution was extracted twice with ethyl acetate. Thecombined organic phase was washed twice with brine and dried with MgSO₄.The solvent was evaporated to give a light brown gum which was dissolvedin CH₂Cl₂, evaporated to a foam, dissolved in ethyl acetate, andevaporated again to givemethyl-(1S,2R,3S)-3-(2-hydroxy-4-methoxyphenyl)-1-(3,4methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylateas light reddish-brown foam (7.08 g, 90%).

(ii). (+)(1S,2R,3S)-3-[2-(2-Hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid ethylene diamine salt (2:1) (Compound (i))

To 463.0 g (21.7% wt/wt, 203.8 mmol) of a toluene solution ofmethyl-(1S,2R,3S)-3-(2-hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylatewas added 425 mL of toluene, 70 g (496 mmol) of potassium carbonate (325mesh) and 183 (2.04 mol) of ethylene carbonate. The resulting mixturewas heated to approximately 110° C. over a period of 60 minutes thenheld at this temperature. The progress of the reaction was monitored byHPLC. The reaction was considered complete when less than 1.0% PAR (peakarea ratio) of starting material was detected. After approximately 3hours at or around 110° C., the reaction was cooled to 70° C. and DIwater (700 mL) was added. The mixture was stirred for 15 minutes thenthe aqueous layer was separated. The organic layer was washed with 5%aqueous citric acid solution (500 mL) followed by DI water (500 mL). Theorganic phase was separated then concentrated under reduced pressure toa viscous oil. The concentrate was diluted with methanol (300 mL) andtetrahydrofuran (500 mL) then a solution of lithium hydroxidemonohydrate (28 g, 654 mmol) dissolved in 300 mL of deionized water wasadded. The resulting solution was heated to reflux (internal temperature62-65° C.) over approximately 15 minutes and maintained at reflux whilemonitoring the reaction progress by HPLC. The reaction was consideredcomplete when no intermediates were detected by in-process HPLCanalysis. After approximately 12 hours at reflux the reaction wasconsidered complete and the resulting mixture cooled to ambienttemperature. DI water (500 mL) was added and the reaction mixtureconcentrated under reduced pressure to a volume of approximately 1 L.Toluene (760 mL) followed by citric acid (150 g, 833 mmol) was added tothe resulting solution and the mixture stirred for 5 minutes. The bottomaqueous layer was drained and the organic layer was washed twice withaqueous brine solution (600 mL). The organic layer was separated andfiltered to afford 868.8 g of(+)(1S,2R,3S)]-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylendioxyphenyl)-5-propoxyindane-2-carboxylicacid as a solution in toluene. HPLC wt/wt assay indicated 11.2% wt/wt(+)(1S,2R,3S)]-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylendioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid.

An analytical sample could be obtained by concentration of the toluenein vacuo and recrystallization from 2-propanol. m.p. 125-127° C.

A toluene solution of(+)(1S,2R,3S)]-3-[2-(2-hydroxyeth-1-yloxy)-4-methoxyphenyl]-1-(3,4-methylendioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid (868.8 g @ 11.2% wt/wt, 192.5 mmol) was concentrated under reducedpressure to a volume of approximately 200 mL. Distillation wasdiscontinued and 2-propanol (500 mL) was added to the concentrate. Theorganic solution was concentrated again under reduced pressure to avolume of approximately 200 mL. Distillation was discontinued and2-propanol (500 mL) was added to the concentrate. The resulting solutionin 2-propanol was allowed to stir at ambient temperature forapproximately 15 minutes to obtain a homogeneous mixture then dilutedwith an additional 1000 mL of 2-propanol. The resulting solution washeated to approximately 60° C. over a period of 15-20 minutes under agentle purge of nitrogen. Heating was discontinued and ethylene diamine(11.6 g, 99.5+%, 192.5 mmol) was added. The reaction mixture was cooledto 30-35° C. over a period of 4 hours. As the solution cooled to 57° C.,precipitation of the title compound occurred. The resulting slurry wasstirred at ambient temperature for approximately 12 hours then cooled to0° C. an additional 3 hours before isolation of the title compound viafiltration. The product was washed with 3 portions of 2-propanol (300mL) followed by hexanes (600 mL) chilled to 0-5° C. The product wasdried in the vacuum oven for approximately 16 hours at 20-25° C. toafford 91.6 g. (87%) of the title compound.

Anal Calcd. for C₃₀H₃₄NO₈ C, 67.15; H, 6.39; N, 2.61. Found, C, 67.2;H,6.48; N, 2.67.

Example 3

Corresponding to Scheme 3

(4S)-4-[3′-Prop-1-yloxy)phenyl]-7-methoxy-3,4-dihydrocoumarin (Compound(c)) (i).(4S)-3-[(E)-3′-(3-propyloxyphenyl)2′-propenoyl]-4-phenyl-2-oxazolidinone

A 500 mL 3-necked flask containing 150 mL of anhydrous THF and 15.9 g(0.098 mol) of (4S)-4-phenyl-2-oxazolidinone was cooled to −73° C. Tothis solution was added 1.3 equiv. of lithium bis(trimethylsilyl)amideat −73° C. under nitrogen with constant stirring. The solution wasstirred at −73° C. for 45 min then allowed to warm to −30° C. when(E)-3-(3′-propyloxyphenyl)-2-propenoyl chloride was added. The solutionwas stirred at −60° C. for 1 hr then allowed to warm to 0° C. andstirred for 1 hr. The reaction was quenched by pouring into water. Thereaction mixture was diluted with 500 mL ethyl acetate and the organiclayer was separated. The aqueous layer was washed with ethyl acetate(3×100 mL). The combined organic layer was washed with 2% NaOCl (3×50mL) then dried over MgSO₄ and concentrated to yield a clean yellow oil.This material was recrystallized from EtOAc/hexanes to yield 12.3 g ofproduct: 0.035 mol (46% yield); ¹H NMR (CDCl₃) δ7.8 (q, 2 H); 6.9-7.4(m, 9 H), 5.5 (dd, 1 H), 4.7 (t, 1 H), 4.3 (dd, 1 H), 3.9 t (2 H), 1.8(m, 2 H), 1.0 (t, 3 H); ¹³C NMR (CDCl₃) δ164.7, 159.4, 153.8, 146.7,139.0, 135.8, 129.8, 129.2, 128.7, 126.0, 121.2, 117.2, 117.0, 114.0,70.0, 69.6, 57.9, 22.6, 10.6 ppm.

(ii)(3′S)-(4S)-3-[3′-(3-Propyloxyphenyl)-3′-(4-methoxy-2-benzyloxyphenyl)-1-oxo-propyl]-4-phenyl-2-oxazolidinone

Cuprous bromide-dimethyl sulphide complex (1.648 g, 8 mmol) was added to21 mL THF and 9 mL of dimethylsulphide in a 3-necked flask at ambienttemperature. The suspension was stirred at room temperature 10 min oruntil solution occurred. The solution was then cooled to −40° C. and theGrignard reagent in THF (16 mmol) prepared from1-bromo-4-methoxy-2-benzyloxybenzene was added at −40° C. The solutionwas allowed to warm to −10° C. and stirred for 10 min.(4S)-3-[(E)-3′-(3-propyloxyphenyl)2′-propenoyl]-4-phenyl-2-oxazolidinone(10 mmol) dissolved in 6 mL of dry THF was added over 20 min. Thereaction mixture was allowed to stir for 60 min, then was quenched bypouring into aqueous ammonium chloride and extracted with ethyl acetate(3×100 mL). The combined organic layer was dried (MgSO₄) thenconcentrated to yield 5.0 g of crude product.

The crude product was flashed over hexanes/ethyl acetate (7/3, v/v) toyield 3.78 g (0.0067 mol, 67% yield) of a major isomer and 0.71 g(0.00126 mol, 12% yield): for the major isomer, 124-125° C.; ¹H NMR(CDCl₃) δ7.3-6.4 (m, 17 H), 5.28 (dd, 1 H), 4.9 (m, 3 H), 4.5 (t, 1 H),4.15 (dd, 1 H), 3.57-3.85 (m, 7 H), 1.77 (m, 2 H), 0.99 (s, 3 H). ¹³CNMR (CDCl₃) δ171.1, 159.3, 159.04, 156.76, 153.74, 145.2, 139.0, 139.9,129.1 (2H), 129.0 (2H), 128.4 (2 H), 127.65, 127.3 (2 H), 125.6, 124.6,120.3, 114.5, 112.2, 104.4, 100.1, 70.0, 69.9, 69.24, 57.6, 55.3, 40.0,39.5, 22.6, 10.6 ppm; mass spec (m/z) 565 (M⁺). Anal. Calcd. forC₃₅H₃₅NO₆: C, 74.32; H, 6.24; N, 2.48. Found C, 74.29; H, 6.27; N, 2.50.

(iii) (4S)-4-[3-Prop-1-yloxy)phenyl]-7-methoxy-3,4-dihydrocoumarin(Compound (c))

(3′S)-(4S)-3-[(E)-3′-(3-propyloxyphenyl)-(4-methoxy-2-benzyloxyphenyl)-1-oxo-propyl]-4-phenyl-2-oxazolidinone(0.564 g, 1 mmol) was dissolved in 100 mL of EtOAc and kept underhydrogen pressure (70 psi) with 10% Pd/C as catalyst for 18 hr. Thecrude reaction mixture was filtered and the ethyl acetate was replacedwith toluene and 10% triethylamine. The solution was heated under refluxfor 1 hr where TLC indicated the disappearance of starting material. Thecrude reaction mixture was filtered and flash chromatographed to yield0.19 g of the desired product (Compound (c)).

Example 4

Corresponding to Scheme 3

3S,4S-3-(1′-Piperonylalcohol)-4-[3-(prop-1-yloxy)phenyl]-7-methoxy-3,4-dihydrocoumarin(Compound (d)) (i)(3′S)-(4S)-3-[2′-Hydroxymethyl(3,4-methylenedioxy)phenyl)-3′-(3-propyloxyphenyl)-3′-(4-methoxy-2-benzyloxyphenyl)-1-oxo-propyl]-4-phenyl-2-oxazolidinone

Cuprous bromide-dimethyl sulphide complex (3.5 g, 0.017 mol) wasdissolved in 42 mL of THF and 20 mL dimethyl sulphide. The suspensionwas allowed to stir 10 min until dissolution occurred. The Grignardreagent (0.034 mol) prepared from 1-bromo-4-methoxy-2-benzyloxybenzenein THF was added at −40° C. The solution was allowed to warm to −10° C.and stir 10 minutes.(4S)-3-[(E)-3′-(3-propyloxyphenyl)2′-propenoyl)]phenyl-2-oxazolidinone(prepared as described in Example 3 (i)) (0.023 mol) in dry THF, wasadded at −20° C. The reaction mixture was allowed to stir at −20° C. for30 min then cooled to −40° C. Piperonal (5.1 g, 0.034 mol) in 5 mL THFwas added over 20 min and the solution was allowed to stir at roomtemperature 18 hr. The reaction mixture was quenched by pouring intoaqueous ammonium chloride and extracted with ethyl acetate (3×100 mL).The combined organic layer was dried (MgSO₄) then concentrated to yieldcrude isomer oily product. The product was purified by chromatographywith silica gel using 7/3 (hexanes/ethyl acetate, v/v) to furnish 2.4 gof each isomer (30% yield). Isomer one: mp 137-139° C.; mass spec (m/z)716 (M+H)⁺; ¹H NMR (CDCl₃) δ7.6 (d, 1 H, J=8.5 Hz) 7.36-6.5 (m, 20 H),5.9 (m, 2 H), 5.64 (dd, 1 H), 5.11-44.7 (m, 8 H), 3.8 (m, 5 H), 1.76 (m,2 H), 1.0 (t, 3 H, J=7.4 Hz); ¹³C NMR (CDCl₃) δ175.6, 159.7, 158.9,157.5, 152.8, 147.5, 146.5, 143.4, 138.2, 137.0, 136.9, 129.0 (2),128.9, 128.5, 128.3, 127.8, 127.5 (2 H), 127.3, 125.7, 124.9 (2), 121.5,121.1, 118.7, 114.5, 113.5, 108.0, 106.5, 105.0, 100.9, 100.5, 72.1,70.3, 69.9, 69.6, 69.4, 57.2, 55.3, 50.8, 22.6; 10.6 ppm. Calcd forC₄₃H₄₁NO₉: C, 72.15; H, 5.77; N, 1.96. Found: C, 72.14; H, 5.79; N,1.91.

Isomer two: mp 163-165° C.; mass spec (m/z) 716 (M+H)⁺; ¹H NMR (CDCl₃)δ7.7 (d, 1 H, J=8.5 Hz) 7.34-6.5 (m, 20 H), 5.9 (m, 2 H), 5.5 (dd, 1 H),5.24-4.6 (m, 5 H), 4.14-3.6 (m, 7 H), 1.77 (m, 2 H), 1.0 (t, 3 H, J=7.4Hz); ¹³C NMR (CDCl₃) δ174.1, 159.4, 159.3, 156.8, 152.7, 146.6, 147.4,143.0, 137.0, 137.9, 136.6, 129.5, 128.5 (2 H), 128.0 (2 H), 127.5,127.1 (2 H), 128.7, 128.3, 124.7, 120.5, 118.4, 115.0, 112.6, 107.9,105.9, 104.5, 100.6, 72.2, 70.1, 69.6, 69.2, 57.1, 55.2, 52.5, 42.08,22.6, 10.5 ppm. Calcd for C₄₃H₄₁NO₉: C, 72.15; H, 5.77; N, 1.96. Found:C, 71.77; H, 5.75; N, 1.95.

(ii).3S,4S-3-(1′-Piperonylalcohol)-4-[3-(prop-1-yloxy)phenyl]-7-methoxy-3,4-dihydrocoumarin(Compound (d))

The starting material,(3′S)-(4S)-3-[2′-hydroxymethyl(3,4-methylenedioxy)phenyl)-3′-(3-propyloxyphenyl)-3′-(4-methoxy-2-benzyloxyphenyl)-1-oxo-propyl]-4phenyl-2-oxazolidinone(1.3 g, 1.8×10⁻³ mol), was dissolved in 60 mL of ethyl acetate and keptunder 10 psi of hydrogen pressure for 18 h with 0.6g of 10% palladium oncarbon. The reaction mixture was filtered then heated under refluxingethyl acetate for 1 h. The solvent was removed and the crude product waschromatographed to yield 0.52 g of the title compound.

Example 5

Corresponding to Scheme 1

(+)(1S,2R,3S)-3-(2-Carboxymethoxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylicacid disodium salt (i). 4-[3′-(benzyloxy)phenyl]-7-methoxycoumarin (acompound of Formula (b))

4-[3′-(hydroxy)phenyl]-7-methoxycoumarin (prepared as in Example 1 (ii)(268 g) and 95% sodium methoxide (102 g) were dissolved in methanol(3.00 L) and stirred while heating to 45° C. Benzyl bromide (314 g) wasadded and the reaction was heated to 60° C. A thick precipitate formedin the pink reaction mixture. After 3 hours, the slurry was cooled in anice-water bath and filtered to collect the product, which was washedwith methanol (500 mL) and water (1.0 L), then dried under vacuum (20inches of Hg) at 70° C. to give4-[3-(benzyloxy)phenyl]-7-methoxycoumarin (320 g, 89%).

300 MHz ¹H NMR (CDCl₃) δ3.88 (s, 3 H), 5.12 (s, 2 H), 6.21 (s, 1 H),6.76 (dd, J₁=2 Hz, J₂=9 Hz, 1 H), 6.89 (d, J=2 Hz, 1 H), 7.02 (m, 2 H),7.12 (dd, J₁=2 Hz, J₂=8 Hz, 1 H), 7.33 (d, J=9 Hz, 1 H) 7.41 (m, 6 H).

(ii).4S-4-[3′-(benzyloxy)phenyl]-7-methoxy-3,4-dihydrocoumarin (acompound of Formula (c))

A clean 500 mL autoclave is charged with4-[3′-(benzyloxy)phenyl]-7-methoxycoumarin (35.8 g; 0.10 mol), abs.methanol (275 mL),(bicyclo[2.2.1]hepta-2,5diene)[(2S,3S)-bis(diphenylphosphino)butane]rhodium(I)perchlorate (727 mg; 1.0 mmol; 1 mol %) and 4 N NaOH (50 mL; 0.2 mol; 2eq). The sealed vessel is purged with 3×400 psi N₂ and 3×400 psi H₂. Thestirred reaction is run at 50° C., 400 psi H₂ for 18-24 h, after whichit is cooled and removed from the vessel. The methanol solution isconcentrated in vacuo to near dryness. The residual brown oil isdissolved in H₂O (250 mL) and washed with toluene (2×100 mL). Thetoluene phases are combined and washed with 1 N NaOH (50 mL). The 1 NNaOH phase is combined with the original aqueous phase. This isacidified to pH 1-2 with 6 N HCl and extracted with toluene (3×200 mL).The combined toluene extracts are washed with sat. NaCl soln (200 mL),dried over MgSO₄ (25 g), filtered, and concentrated in vacuo to 150-200mL. The toluene solution is treated with p-toluenesulfonic acidmonohydrate (1.0 g) and heated to 50° C. for 1 h, or until HPLCindicates that lactonization is complete. The solution is cooled, washedwith sat. NaCl soln (150 mL), dried over MgSO₄ (20 g), filtered,slurried with florisil (5 g) for 15 min, filtered, and concentrated invacuo to near dryness as a clear oil. Addition of hexanes (100 mL), tothe stirred oil results within 15 min the title compound as a whitefilterable solid (30.3 g; 84% yield). Chiral HPLC indicates 84% ee.

300 MHz ¹H NMR (CDCl₃) δ2.99-3.08 (overlapping quartets, 2 H), 3.81 (s,3 H), 4.25 (br t, J=7 Hz, 1H), 5.02 (s, 2 H), 6.62-6.91 (m, 6 H),7.24-7.42 (m, 6 H).

(iii). 4S-4-[3′-(hydroxy)phenyl]-7-methoxy-3,4-dihydrocoumarin (acompound of Formula (c))

4S-4-[3′-(benzyloxy)phenyl]-7-methoxy-3,4-dihydrocoumarin (7.09 g), 10%Pd/C (Degussa type E101 NE/W, 50% water wet, 1.45 g), and ethyl acetate(225 mL) were charged to a 500 mL flask on a Parr shaker, purged 5 timeswith 40 psi H₂, then shaken for 48 hours at 40° C. under 40 psi H₂. Thereaction was filtered to remove the catalyst, concentrated, and driedunder vacuum to yield4S-4-[3′-(hydroxy)phenyl]-7-methoxy-3,4-dihydrocoumarin as an oilcontaining some residual ethyl acetate (6.00 g).

300 MHz ¹H NMR (CDCl₃) δ2.88-3.04 (overlapping quartets, 2 H), 3.75 (s,3 H), 4.18 (br t, J=7 Hz, 1H), 6.59-6.66 (m, 3 H), 6.74 (dd, J₁=8 Hz,J₂=2 Hz, 1 H), 6.85-6.90 (m, 2 H), 7.14 (t, J=8 Hz, 1 H).

(iv).3S,4S-3-(1′-Piperonylalcohol)-4-[3′-(hydroxy)phenyl]-7-methoxy-3,4-dihydrocoumarin(a compound of Formula (d))

4S-4-[3′-(hydroxy)phenyl]-7-methoxy-3,4dihydrocoumarin (20.0 g) wasdissolved in methylene chloride (360 mL) with heating. The resultingsolution was cooled to −73° C. (internal temperature) and treatedsequentially with neat TiCl₄ (33.8 g), N,N-diisopropylethylamine (24.4g), and piperonal (11.2 g) in CH₂Cl₂ (15 mL). Each addition took about30 minutes, and the temperature was always kept a @ ≦−72° C. Afterstirring 30 minutes, the reaction was quenched with saturated aqueousNH₄Cl (200 mL) and water (200 mL) and warmed to 0° C. The layers wereequilibrated and separated. The aqueous layer was extracted twice withmethylene chloride (2×100 mL) and the combined organic phases werewashed three times with water (3×300 mL) and with brine (300 mL). Thesolution was dried with MgSO₄ and concentrated to give a brittle foam(31.1 g) consisting of an approximately 5:1 mixture of the two alcoholdiastereomers of3S,4S-3-(1′-Piperonylalchohol)-4-[3-(hydroxy)phenyl]-7-methoxy-3,4dihydrocoumarin.MS (electrospray) m/z 443 (M+Na)⁺, 403 (M+H−H₂O)⁺.

(v).1S,2R,3S-1-Piperonyl-2,3-(7′-methoxy-2′,3′-dihydrocoumarinyl)-5-(hydroxyl)indane(a compound of Formula (e))

A solution of3S,4S-3-(1′-Piperonylalcohol)-4-[3′-(hydroxy)phenyl]-7-methoxy-3,4-dihydrocoumarin(31.1 g) in toluene (620 mL) at 87° C. (internal temperature) wastreated with 85% H₃PO₄ (44.4 g). The reaction was stirred at about 80°C. for 9.5 hours, then cooled to 20° C. and poured into a separatoryfunnel. The residue in the flask was rinsed into the funnel with hottoluene (2×100 mL) and the toluene solution was diluted with 100 mL ofethyl acetate. The solution was washed twice with water (3×250 mL)followed by saturated aqueous NaCl (150 mL). The organic layer was driedwith MgSO₄ and concentrated almost to dryness. Ethanol (20 mL) was addedand the mixture was again concentrated almost to dryness. The resultingslurry was triturated with another 20 mL of ethanol, then filtered tocollect the light yellow solid. The flask was rinsed into the funnelwith ethanol (20 mL) and the filter cake was air-dried to give 14.3 g(48% for the combined aldol/cyclization) of a 3.5:1 mixture of1S,2R,3S-1-Piperonyl-2,3-(7′-methoxy-2′,3′-dihydrocoumarinyl)-5-(hydroxyl)indaneand a regioisomeric cyclization product.

300 MHz ¹H NMR,1S,2R,3S-1-Piperonyl-2,3-(7′-methoxy-2′,3′-dihydrocoumarinyl)-5-(hydroxyl)indane(CDCl₃) δ2.99 (dd, J₁=15 Hz, J₂=11 Hz, 1 H), 3.81 (s, 3 H), 4.40(overlapping doublets, looks like triplet; higher field J=15 Hz, 1 H;lower field J=11 Hz, 1 H), 4.92 (s, 1 H), 5.94 (d, J=3 Hz, 2 H),6.70-6.80 (m, 5 H), 6.86-6.90 (m, 2 H), 7.28 (s or fine d overlappingwith CHCl₃, 1 H), 7.71 (d, J=8 Hz, 1 H).

300 MHz ¹H NMR, regioisomer (CDCl₃) δ2.99 (dd, J₁=15 Hz, J₂=11 Hz, 1 H),3.80 (s, 3 H), 4.37 (d, J=15 Hz, 1 H) 4.53 (d, J=11 Hz, 1 H), 4.57 (s, 1H), 5.94 (s, 2 H), 6.70 (d, J=2 Hz, 1 H), 6.73 (dd, J₁=10 Hz, J₂=2 Hz, 1H), 6.81 (d, J=8 Hz, 2 H), 6.88 (s, 1 H), 6.98 (d, J=8 Hz, 1 H),7.29-7.37 (m, 2 H), 7.74 (d, J=9 Hz, 1 H).

(vi).1S,2R,3S-1-Piperonyl-2,3-(7′-methoxy-2′,3′-dihydrocoumarinyl)-5-(prop-1-yloxy)indane(a compound of Formula (e))

1S,2R,3S-1-Piperonyl-2,3-(7′-methoxy-2′,3′-dihydrocoumarinyl)-5-(hydroxyl)indane(14.3 g) was dissolved in THF (160 mL) and stirred in a 20° C. waterbath. The clear solution was treated sequentially withtriphenylphosphine (14.2 g), 1-propanol (3.24 g), and diisopropylazodicarboxylate (11.4 g). After 1 hour, the reaction was quenched withwater (100 mL). The resulting precipitate was collected by filtration,washed with acetonitrile (20 mL), and triturated with 90 mL ofacetonitrile to yield 8.1 g (51%) of1S,2R,3S-1-Piperonyl-2,3-(7′-methoxy-2′,3′-dihydrocoumarinyl)-5-(prop-1-yloxy)indane.This compound is then utilized as in Example 1 (vii) and forward toyield final product.

(via).1S,2R,3S-1-Piperonyl-2,3-(7′-methoxy-2′,3′-dihydrocoumarinyl)-5-(prop-1-yloxy)indane(a compound of Formula (e)); (alternate preparation)

To a solution of1S,2R,3S-1-Piperonyl-2,3-(7′-methoxy-2′,3′-dihydrocoumarinyl)-5-(hydroxyl)indane(100 mg) and Pd(DIPHOS)₂ (11 mg) in THF (2.0 mL) was added allyl methylcarbonate (88 mg). The mixture was stirred at 50° C. overnight afterwhich HPLC showed 60%1S,2R,3S-1-Piperonyl-2,3-(7′-methoxy-2′,3′-dihydrocoumarinyl)-5-(allyloxyl)indane(compared versus an authentic sample prepared by another method).

1S,2R,3S-1-Piperonyl-2,3-(7′-methoxy-2′,3′-dihydrocoumarinyl)-5-(allyloxyl)indane(100 mg) was suspended in ethyl acetate (5 mL) with 10% Pd/C (Degussatype E101 NE/W, 50% water wet, 20 mg) in a Parr bottle. The mixture wasshaken at 50° C. under 20 psi hydrogen for 1.5 hours. HPLC showedcomplete conversion to1S,2R,3S-1-Piperonyl-2,3-(7′-methoxy-2′,3′-dihydrocoumarinyl)-5-(prop-1-yloxy)indane.This compound is then utilized as in Example 1 (vii) and forward toyield final product.

While the preferred embodiments of the invention are illustrated by theabove, it is understood that the invention is not limited to the preciseinstructions herein disclosed and that the right to all modificationscoming within the scope of the following claims is reserved.

What is claimed is:
 1. A compound having Formula (13):

wherein three of A, B, C and D are carbon atoms and one is a nitrogenatom; R³ and R⁴ are independently H, OH, protected OH, C₁₋₈alkoxy, Br,F, I, Cl, CF₃ or C₁₋₆alkyl; and R is H, OH, C₁₋₅alkoxy or a protectedoxy group.
 2. A compound having Formula (16):

wherein three of A, B, C and D are carbon atoms and one is a nitrogenatom; R³ and R⁴ are independently H, OH, protected OH, C₁₋₈alkoxy, Br,F, I, Cl, CF₃ or C₁₋₆alkyl; R is H, OH, C₁₋₅alkoxy or a protected oxygroup and X_(c) is a chiral auxiliary group.
 3. The compound accordingto claim 2 wherein said chiral auxiliary group is selected from thegroup consisting of a 5-methyl-2-(1-methyl-1-phenyl-ethyl)-cyclohexyloxygroup, a bornane-2,10-sultam group, a 4-substituted or 4,5-substituted2-oxo-oxazolidin-3-yl group and a 4-substituted or 4,5-substituted2-oxo-imidazolidin 1-yl group.
 4. The compound according to claim 2wherein said chiral auxiliary group is selected from the groupconsisting of 5-methyl-2-(1-methyl-1-phenyl-ethyl)-cyclohexyloxy,10,10-dimethyl-3-thia-4-aza-tricyclo[5.2.1.0^(1.5)]decane3,3-dioxo-4-yl, 4-phenyl-2-oxo-oxazolidin-3-yl,4-isopropyl-2-oxo-oxazolidin-3-yl, and3,4-dimethyl-5-phenyl-2-oxo-imidazolidin-1-yl.
 5. A compound havingFormula (25):

wherein three of A, B, C and D are carbon atoms and one is a nitrogenatom; R³ and R⁴ are independently H, OH, protected OH, C₁₋₈alkoxy, Br,F, I, Cl, CF₃ or C₁₋₆alkyl; R is H, OH, C₁₋₅alkoxy or a protected oxygroup and X_(c) is a chiral auxiliary group.
 6. The compound accordingto claim 5 wherein said chiral auxiliary group is selected from thegroup consisting of a 5-methyl-2-(1-methyl-1-phenyl-ethyl)-cyclohexyloxygroup, a bornane-2,10-sultam group, a 4-substituted or 4,5-substituted2-oxo-oxazolidin-3-yl group and a 4-substituted or 4,5-substituted2-oxo-imidazolidin 1-yl group.
 7. The compound according to claim 5wherein said chiral auxiliary group is selected from the groupconsisting of 5-methyl-2-(1-methyl-1-phenyl-ethyl)-cyclohexyloxy,10,10-dimethyl-3-thia-4-aza-tricyclo[5.2.1.0^(1.5)]decane3,3-dioxo-4-yl, 4-phenyl-2-oxo-oxazolidin-3-yl,4-isopropyl-2-oxo-oxazolidin-3-yl, and3,4-dimethyl-5-phenyl-2-oxo-imidazolidin-1-yl.
 8. A process for thepreparation of a compound of Formula (19),

wherein three of A, B, C and D are carbon atoms and one is a nitrogenatom; R¹ is

 where R³ and R⁴ are independently H, OH, protected OH, C₁₋₈alkoxy, Br,F, I, Cl, CF₃ or C₁₋₆alkyl and R⁵ is —OCH₂CO₂H; R² is

 where R³ and R⁴ are as indicated above and Z is H, OH, or C₁₋₅alkoxy;or a pharmaceutically acceptable salt thereof, wherein said methodcomprises converting a compound of Formula (13),

wherein three of A, B, C and D are carbon atoms and one is a nitrogenatom; R³ and R⁴ are independently H, OH, protected OH, C₁₋₈alkoxy, Br,F, I, Cl, CF₃ or C₁₋₆alkyl; and R is H, OH, C₁₋₅alkoxy or a protectedoxy group into the compound of Formula (19), and thereafter optionallyforming a pharmaceutically acceptable salt thereof.
 9. A process for thepreparation of a compound of Formula (19),

wherein three of A, B, C and D are carbon atoms and one is a nitrogenatom; R¹ is

 where R³ and R⁴ are independently H, OH, protected OH, C₁₋₈alkoxy, Br,F, I, Cl, CF₃ or C₁₋₆alkyl and R⁵ is —OCH₂CO₂H; R² is

 where R³ and R⁴ are as indicated above and Z is H, OH, or C₁₋₅alkoxy;or a pharmaceutically acceptable salt thereof, wherein said methodcomprises converting a compound of Formula (16),

wherein three of A, B, C and D are carbon atoms and one is a nitrogenatom; R³ and R⁴ are independently H, OH, protected OH, C₁₋₈alkoxy, Br,F, I, Cl, CF₃ or C₁₋₆alkyl, R is H, OH, C₁₋₅alkoxy or a protected oxygroup and X_(c) is a chiral auxiliary group; into the compound ofFormula (19), and thereafter optionally forming a pharmaceuticallyacceptable salt thereof.
 10. The process according to claim 9 whereinsaid chiral auxiliary group is selected from the group consisting of a5-methyl-2-(1-methyl-1-phenyl-ethyl)-cyclohexyloxy group, abornane-2,10-sultam group, a 4-substituted or 4,5-substituted2-oxo-oxazolidin-3-yl group and a 4-substituted or 4,5-substituted2-oxo-imidazolidin 1-yl group.
 11. The process according to claim 9wherein said chiral auxiliary group is selected from the groupconsisting of 5-methyl-2-(1-methyl-1-phenyl-ethyl)-cyclohexyloxy,10,10-dimethyl-3-thia-4-aza-tricyclo[5.2.1.0^(1.5)]decane3,3-dioxo-4-yl, 4-phenyl-2-oxo-oxazolidin-3-yl,4-isopropyl-2-oxo-oxazolidin-3-yl, and3,4-dimethyl-5-phenyl-2-oxo-imidazolidin-1-yl.
 12. A process for thepreparation of a compound of Formula (19),

wherein three of A, B, C and D are carbon atoms and one is a nitrogenatom; R¹ is

 where R³ and R⁴ are independently H, OH, protected OH, C₁₋₈alkoxy, Br,F, I, Cl, CF₃ or C₁₋₆alkyl and R⁵ is —OCH₂CO₂H; R² is

 where R³ and R⁴ are as indicated above and Z is H, OH, or C₁₋₅alkoxy;or a pharmaceutically acceptable salt thereof, wherein said methodcomprises converting a compound of Formula (25),

wherein three of A, B, C and D are carbon atoms and one is a nitrogenatom; R³ and R⁴ are independently H, OH, protected OH, C₁₋₈alkoxy, Br,F, I, Cl, CF₃ or C₁₋₆alkyl; R is H, OH, C₁₋₅alkoxy or a protected oxygroup and X_(c) is a chiral auxiliary group; into the compound ofFormula (19), and thereafter optionally forming a pharmaceuticallyacceptable salt thereof.
 13. The process according to claim 12 whereinsaid chiral auxiliary group is selected from the group consisting of a5-methyl-2-(1-methyl-1-phenyl-ethyl)-cyclohexyloxy group, abornane-2,10-sultam group, a 4-substituted or 4,5-substituted2-oxo-oxazolidin-3-yl group and a 4-substituted or 4,5-substituted2-oxo-imidazolidin 1-yl group.
 14. The process according to claim 12wherein said chiral auxiliary group is selected from the groupconsisting of 5-methyl-2-(1-methyl-1-phenyl-ethyl)-cyclohexyloxy,10,10-dimethyl-3-thia-4-aza-tricyclo[5.2.1.0^(1.5)]decane3,3-dioxo-4-yl, 4-phenyl-2-oxo-oxazolidin-3-yl,4-isopropyl-2-oxo-oxazolidin-3-yl, and3,4-dimethyl-5-phenyl-2-oxo-imidazolidin-1-yl.